Substituted pyrido(1,2,3-de)-1,4-benzoxazines

ABSTRACT

Anti-microbial agents which are 2,3-dihydro-3-substituted-7-oxopyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acids are prepared by condensation of benzoxazines with ethoxymethylene malonate esters followed by ring closure with poly phosphoric acid and hydrolysis of the resulting esters.

United States Patent Gerster [4 1 May 13, 1975 Chem.

SUBSTITUTED PYRIDO( i,2,3-DE)-l,4-BENZOXAZINES John F. Gerster,Woodbury, Minn.

Riker Laboratories, Inc., Northridge, Calif.

Filed: Feb. 11, 1974 App]. No; 440,951

Inventor:

Assignee:

US. Cl 260/244; 424/248 Int. Cl C07d 87/00 Field of Search 260/244;424/248 References Cited OTHER PUBLICATIONS Abst. 72. 90686(s)(l970)3-oxoloxajulolidines" Teacher et al.

Primary ExaminerAlbert T. Meyers Assistant Examiner-Douglas W. RobinsonAttorney, Agent, or Firm-Alexander, Sell, Steldt & DeLaHunt [57]ABSTRACT 26 Claims, No Drawings SUBSTITUTEDPYRIDO(1,2,3-DE)-l,4-BENZOXAZINES BACKGROUND OF THE INVENTION Thisinvention relates to derivatives of the heterocyclic system known aspyridol l ,2,3-de]benzoxazine. More specifically, it relates to2,3dihydro3 substituted-7-oxo-7H-pyrido[ l,2,3-de l ,4-benzoxazine-fi-carboxylic acids, their salts and esters thereof. Thesecompounds are optionally substituted at the 3 (three) position by loweralkyl groups and on the benzo ring portion by a variety of substituents.A further aspect of this invention relates to the use of these compoundsas anti-microbial agents in pharmaceutically acceptable compositions.

DESCRIPTION OF THE PRIOR ART The basic ring structure ofpyrido[l,2,3-de]-1,4- benzoxazine is known. Fischer, Ber. 16,7 l2(1883), reports a compound with the structure 2-oxo-3,6,7-trihydro-5H-pyrido[1,2,3-de1-l,4-benzoxazine. The compound2,3,6,7-tetrahydro-5H-pyrido[ l,2,3-de]- l,4-benzoxazine is reported bylsler, Helv. Chim. Acta, 27,1756 (1944). Dickey and McNally (US. Pat.No. 2,448,869) list a number of compounds as intermediates having thesame basic ring structure which they name astrimethylenebenzomorpholines. The compounds of this invention differfrom and are not believed to be suggested or anticipated by any of theseknown compounds.

This invention relates to derivatives of 2,3-dihydro-7-oxo-7H-pyrido[l,2,3-de]-l,4 benzoxazine. The structure and numberingmethod for this heterocyclic ring system are shown below:

The compounds of the invention are represented by the followingstructural formula:

0 0 2 n 3 Formula I R COR wherein R is hydrogen. a cation or loweralkyl, R is hydrogen or lower alkyl, R is lower alkyl, lower alkoxy,halogen or nitro, ri is zero to three and when R is nitro, R is methylor ethyl.

Lower alkyl" or lower alkoxy as used herein means alkyl or alkoxy,respectively, having from I to 4 carbon atoms in straight or branchedchain configuration.

Compounds of the invention wherein R is hydrogen, which are acids, arepreferred as anti-microbial agents. Salts of said acids are equivalentto the acids. Compounds wherein R is lower alkyl are primarily useful asintermediates for the preparation of the corresponding acids, althoughsome of these compounds also exhibit anti-microbial activity.

Cations as defined herein are pharmaceutically acceptable cations whichform salts with the compounds wherein R is hydrogen, such as alkalimetal, alkaline earth, aluminum, iron and other metal and amine salts.Such pharmaceutically acceptable salts are known to be equivalent to theacids for many purposes, and may even offer advantages in absorption,formulation and the like.

The anti-microbial activity of these compounds can be demonstrated bythe standard plate dilution method for bacterial susceptibility ofantibiotics, (English Antibiot. Chemother. Vol. l, 118, I951 The culturemedium employed permits susceptibility testing of fastidiousmicroorganisms towards antibiotics, sulfonamides and otherchemotherapeutic agents. Tryptone soy agar (oxoid) of the followingcomposition is the culture medium.

Oxoid tryptone l. Oxoid soypeptone Sodium chloride Oxoid agar-agar No.3 1. Water Using this test, the compounds of the invention have beenfound to have a broad spectrum of activity against gram-positive andgram-negative microorganisms.

The compounds of the invention are active against microorganisms eitherin the absence or presence of ten percent horse serum.

In the test procedure, the amount of a compound required to givecomplete inhibition or no inhibition of the microbial growth on the agarplates was determined. The compound selected for evaluation is added tothe agar medium to give concentrations of one, ten and one hundredmilligrams per liter. A series of plates with these concentrations isprepared. Plates containing agar alone are included as controls. Tenpercent horse serum is added to one series of such plates. Aliquots ofbroth culture of each of nine species of micro organisms are innoculatedonto the agar plates contain ing the various compound concentrations andonto the control plates. The plates are incubated at 37 C. in a 10percent carbon dioxide atmosphere for 18 to 25 hours. The microbialgrowth on each plate is read visually, and minimal inhibitoryconcentrations are re corded.

The microorganisms used for this test were:

. Staphylococcus aureus Bacillus sublilus Pseudomonas aeruginosaEscherichia coli Streptococcus sp.*

. Aspergillus niger Candida albicans Mirna polymorpha 9. Herelleavaginicola Strains isolated from dental caries in rats or hamsters atthe National Institute of Dental Health and grown in PFY or APT agar.

All of the compounds of the invention either possess antibacterialactivity towards one or more of the above microorganisms, or are usefulintermediates in the preparation of compounds which exhibit suchactivity.

Many of the compounds of the invention have also shown activity versusanaerobic bacteria, for example Bacreroides sp. and Clostridium welchii.Some compounds have shown activity versus Erwinia amylovora, agram-negative microorganism responsible for the plant disease known asfire blight.

It will be understood by those skilled in the art that the species usedare representative indicator species, as it would be impractical toscreen against all bacteria, It is well known in the art that broadspectrum activity can be predicted on the activity shown againstselected representative bacterial species.

All of the compounds of the invention are active versus microorganismsin vitro or topicallyv In vitro activity is useful in itself, sinceanti-microbial agents may be used for disinfecting and sterilizing, forexample medical and dental equipment, as components of disinfectingsolutions. The preferred compounds of the invention are also active invivo in animals. These compounds exhibit anti-microbial activity whenadminis tered orally to animals. They are excreted in the urine and areeffective antibacterial agents for treatment of urinary tract infectionsin mammals.

The acute oral toxicity of the compounds of the invention is generallymoderate to low compared with the effective oral dose, and they have afair to excellent therapeutic ratio.

Presently preferred compounds of the invention have a broad spectrum ofanti-microbial activity and a good therapeutic ratio (LD /ED Thesecompounds are:

2,3 -dihydro lO-fluoro-3-methyl-7-0xo-7l-lpyrido[1,2,3-de1-1,4-benzoxazine-o-carboxylicacid lO-chlow-2,3-dihydro-3-methyl-7-oxo-7H- pyrido[ l ,2,3-de]- l,4-benzoxazine-6-carboxylic acid 2.3-dihydro-9'fluoro-7-oxo7H-pyrido[1,2,3-de1- benzoxazine-fi-carboxylic acid9-chloro-2,3-dihydro-3-methyl-7-oxo-7H- pyrido[ l ,2,3-de]-l,4-benzoxazine-6-carboxylic acidl-chloro-2,3-dihydro-3,8-dimethyl-7-oxo-7H-pyrido- [l,2,3-de]- l,4-benzoxazine-o-carboxylic acid 2,3-dihydro-3, l0-dimethyl-7-oxo-7H-pyrido[ l ,2,3-

del-l ,4-benzoxazine-6-carboxylic acid 2 O on 0a oca=ctuo OH on n 3 2 a2 3 2 N l H a 4 9-chloro-2,3-dihydro-3,lO-dimethyl-7-oxo7H-pyrido-[l,2,3-de]-l,4-benzoxazine-o-carboxylic acid2,3-dihydro-7-oxo-3,8,lO-trimethyl-7H-pyrido[1,2,3

de] l ,4-benzoxazine-o-carboxylic acid2,3dihydro-3,9-dimethyl-7-oxo-pyrido[ l ,2,3-de]- l ,4-

benzoxazine-o-carboxylic acid and salts thereof.

The compounds of the invention may be formulated by incorporating theminto conventional pharmaceutical carrier materials, either organic orinorganic, for example, in formulating tablets or capsules for oraladministration or liquid preparations suitable, for example, forintraperitoneal application. For in vitro or topical use, simple aqueoussolutions or suspensions are most conveniently employed. For thispurpose, concentrations of the order of I00 parts per million up to 5parts per thousand are suitable. The formulation is used by immersingobjects to be treated therein, or by local application to an infectedarea.

The amount of compound to be used, for example, in the treatment ofaurinary tract infection by oral administration, will be an effectiveamount less than a toxic amount. The amount administered to control theinfection will depend on the species, sex, weight, and physicalcondition of the patient as well as other variable factors. Thisjudgment is well within the skill of the medical art. Usually the amountwill be less than lOO trig/kg. per dose. Conveniently this isadministered in the form of ordinary pharmaceutical preparations such ascapsules, tablets, emulsions, solutions and the like. Excipients,fillers, coatings, etc., are usually employed with tablets or capsules,as is well known in the art.

It is known to the art that anti-microbial agents are used as growthpromoters in various animal and bird species. Although not yet verified,it can be inferred from their antimicrobial activity that the compoundsof this invention can be used for this purpose also. The compounds ofthe invention may also be useful for the control of microbial (e.g.,Erwinia amylovora) infections of plants, e.g., by spraying or dustingformulations of these compounds on the affected area.

Compounds of the invention are prepared by the following reactionsequence:

1 to 5 hour Formula II Polyphosphoric acid 100 I lO Formula III [n theabove reaction sequence a dialkyl ethoxymethylene malonate (illustratedby diethyl ethox' ymethylene malonate) is condensed with a 3,4-dihydro-2H-l,4-benzoxazine of Formula ll by heating without solvent at100 to 200 C. for one to five hours. The novel intermediates thus formedare generally oils which need not be purified for further use in thereaction. Polyphosphoric acid is then added and the solution is heatedto 100 to 140 C. to effect a condensation to the novel intermediates ofFormula [11. The compounds of Formula Ill are included within the scopeof the invention as useful intermediates in the preparation of compoundsof Formula I. The final step is saponification of the esters of Formula[I] to the acids of Formula 1.

Compounds of Formula [I are generally known, or may be prepared byprocedures known to the art. For example, see US. Pat. No. 2,448,869.Compounds of Formula [I may be conveniently prepared by one of thefollowing methods:

EXAMPLE I Diethyl ethoxymethylene malonate (19.8 g., 0.092 mole) isadded to 3,4-dihydro-3,7-dimethyl-2H-l,4- benzoxazine (l5.0 g., 0.092mole) and the solution is heated at ll0 to C. for three hours.Polyphosphoric acid 100 g.) is added and the solution is graduallyheated to C. with occasional stirring. The solution is heated at to C.for one additional hour. The hot solution is poured into 300 ml. water-Procedure A 0\, H o

##(i J ea r @I] wherein R and n are as defined hereinabove.

Procedure B O 0 5R O ClCl-l 5R CH2 HOB 2 @K @g. 6

N0 2 formanide 110 Selective reduction 2 o 2 oc1i ela. Rn R a 'f R HFormula II wherein R and n are as defined hereinabove, M is an alkalimetal and R is lower alkyl.

In procedure A chemical reduction methods using diborane or metalhydrides provide intermediates wherein R is hydrogen.

In procedure B, comprising several known reactions, step 1 is theformation of phenolate salt of orthonitrophenol and step 2 is thedisplacement of halogen (illustrated by chlorine) ofa halomethyl loweralkyl ke tone. Step 3 requires selective hydrogenation of the nitrogroup by catalytic methods, for example using palladium on charcoal orRaney nickel. or chemical methods, for example, iron and acetic acid.This hydro- Analysis: %C 'X H EN Calculated for C H NO,: 66.9 6.0 4.9Found: 66.4 5.9 4.9

EXAMPLE 2 Using the method of Example l diethyl ethoxymethylene malonateis reacted with 3,4-dihydr-6-methoxv 3-methyl-2H-l,4 benzoxazine and theproduct reacted 5 with polyphosphoric acid to provide ethyl 2,3-dihydro-8-methoxy-3-methyl-7-oxo-7H-pyrido-[ ,2,3-de]-l ,4-benzoxazine-(w-carboxylate, m.p. l65-168 C.

EXAMPLE 3 Using the method of Example 1, diethyl ethoxymethylenemalonate is reacted with 6-chl0ro-3,4- dihy'dro-3-methyl-2H- l.4-benzoxazine and the product reacted with polyphosphoric acid toprovide ethyl 8- chloro-Z,3-dihydro-3-methyl-7-oxo-7H pyrido-l1,2,3- de]1 ,4-benzoxazine-6-carboxylate. m.p. 205206 C.

Additional compounds prepared using the method of Example 1 are:

Example No 4 ethyl 9chloro-2.3-dihydro-3-methyl-7-oxo-7H-pyrido[ 1,

The following compounds are prepared using the method of Example 1 byreacting 8-chloro-3,4- dihydro-3-methyl-2H-l ,4-benzoxazine with variousesters of ethoxymethylene malonate as shown:

Example No.

Ethoxy- I methylene Example malonate N0. eater Product of Formula I 7methyl Cl N 8 n-butyl ll 0 C 2 H CH CH CH C N isopropyl I CO CH(CH n-hexl 9 Y 0 (CH CH The following compounds are prepared using the l,l-BGIIZOQ zine method of Example 1 by reacting diethyl ethoxymethylenemalonate with various 1,4-benzoxazines as shown:

TABLE I I Product of Formula I 0 11 l CO2CH2CH3 N on on l [AIM l llCminued 15 H CH l I co ca cu E CH3 N ca ca EXAMPLE 16 Ethyl,3-dihydro-3,9-dimethyl-7-oxo-7H- pyrido[ l,2,3-de]-l,4-benzoxazine-fi-carboxylate is dissolved in excess three percentsodium hydroxide and heated on the steam bath for one hour. The solutionof the sodium salt of 2,3-dihydro-3,9-dimethyl-7-ox0-7H- pyrid0[ l,2,3-de ]-l ,4-benzoxazine-6-carboxylate is treated with decolorizingcharcoal, filtered, then neutralized with concentrated hydrochloricacid. The offwhite solid precipitate is separated by filtration, washedwith water and dried. Recrystallization of 2,3-dihydro-3,Q-dimethyl-7-oxo-7H-pyrido-[ l ,2.3-de]-l ,4-

benzoxazine-G-carboxylic acid from dimethyl formamide gives a whitesolid, m.p. 246-248 C.

Analysis: %C' %H %N Calculated for C l-l No z 64.9 $.l 5.4 Found: 6184.7 5.3

Using the method of Example 16 the following table illustrates compoundsof Formula I which were prepared by hydrolysis of compounds wherein R isethyl.

TABLE III example Melting Point No. Product Compound (in C.)

1 1 0 7 coon 290 291 C d-C hloro-Z B-dihydro-B-mechyl-7-oxo-7Hpyrido[1,2,3-de]-l, -lbenzoxazine-6- carboxylic acid 23-dihydro-7-oxo-7H-pyrido[ l, 2 B-deJ-i,

l-benzoxazine-6-carboxylic acid 235- 3! 1 9 COOH A CH T 111 C0ntinuedEmple Melting Point g2. ggoduct Cgound gin C.) 23-dihydro-3-methyl-7-oxo-7H-pyrido[ l 2 3-de]-l l-benzoxa.zine--6-carboxylic acid 2 3-d ihydro-9-methoxy-3-methyl-7-oxo-7H- COOH pyrido[l 2, 3-de]-l, l-benzoxazine-6- carboxylic acid 23-dinydr0-l0-fluor0-3-mechyl-Y-oxo-Tl-lpyrido[l,2, 3-de]-l,lbenzoxazine-Eicarboxylic acid lO-chloro-Z, 3-dihydro-3-methyl-7-oxo-7H- pyridoEl, 2 3-deJ-l, l-benzoxazine-S- carboxyiic acid0 COOH \/kc 3 9-chloro-2 3-dihydro-3-methy1-7-oxo-7H- pyrido[l, 2,3-de]-l, lbenzoxazine-ticarboxylic acid V 3 i-fluoro-Z3-dihydro-3-methyi-7-oxo-7H- pyridolIl 2 3-de]-1 l-b -:nzoxazine--6-carboxylic acid 12 TABLE v TABLE III continued Acid Product EnterExample i '18 No. Material Ban-pl Melting Point:

at C and in C. 26 I P l95- 97 COOH mp. 300 C.

pyrideELZJ-deJ-IJ- benzoxazine-6- carboxylic 3 H C O N 3 C o 3 H C 2 H C2 O C u on m. l l0-l'42 0.

m.p. l95-l97 C Example No. Product or Formula I m.p. ZEN-266 C.

CODE

m.p. 300- C.

m.p. 219-221 c.

w 3 O H c O 1 l C C 3 H C 2 H C 2 O 3 C H l C M A 0 l l C C 5 4 3 H C 52 H C lw 0 l C mp. 300 c.

I a '28 o C- P 5 7 coon l 3 H C 2 H C 2 o COOl-l mp. ENS-2 4'? C.

N02 8 coon CH CH m.p. 300 C.

TABLE V Qontinued 2 m.p. 2 4Y-2 l9 C.

m.p. l95-l97 C 2 2 3 coon CH3 (kl CH3 CH3 N VK m.p. 2 43-2 65 C. m.p.300 C- O 42 CH CH3 3) C0 CH CH3 00 l CH3 N CH3 u F coon imp. 300 C.

EXAMPLE 44 2,3-Dihydro-3-methyl-7oxo-7H-pyrido[ l ,2,3-del.4-benzoxazine-6-carboxylic acid (3.0 g., 0.072 mole) is dissolved inconcentrated sulfuric acid (30 ml.) and water mixture. The2,3-dihydro-3-methyl-8-nitro-7- 5 oxo-7H-pyrido[ l ,2,3-de l,4-benzoxazine-6- carboxylic acid is a tan solid, mp. 269-27l C.

the solution is cooled to 0 C. with an ice-salt bath. A mixture ofconcentrated (70%) nitric acid (0.77 g.) in 60 Analysis:

concentrated sulfuric acid 3 ml.) is added dropwise CalculaedforcmHmNaou: with stirring while maintaining the reaction temperapound,

ture at 0 to 5 C. The mixture is allowed to warm to room temperature,then poured, with stirring. over ice. The pH of the solution is adjustedby the addition of 65 concentrated ammonium hydroxide to about 1 to 2.The brown solid is separated by filtration, washed with EXAMPLE 45 Whentested by the standard method described here water and recrystallizedfrom a dimethyl formamideinabove. compounds of the invention inhibitgrowth of TABLE VI Microorganism EC PA MP |++++l|l++++l++|ll|++++l+l+++l++++l ++'+++++++++++++l ll ++|I+l+l+||l||lll I ++llllll+llli(ester) 37 (acid) c.) L) \O 00 active inactive SS Streptococcus p SASlaphylrxuu'u: nun-us BS Bacillus Sublllus EC Eschrrirhia roli PAPseudumunns nemginuru MP Minna polymurpha What is claimed is: l. Acompound of the formula 0 0 n 2 c0a R n l wherein R is hydrogen or loweralkyl, R is hydrogen or lower alkyl. R is lower alkyl, lower alkoxy,halogen or nitro and n is zero to three; when R is nitro. R is methyl orethyl, or pharmaceutically acceptable salts of such compounds when R ishydrogen.

2. A compound according to claim 1 wherein R is hydrogen.

3. A compound according to claim 1 wherein R is lower alkyl.

4. A compound according to claim 1 wherein n is one or two.

5. A compound according to claim 1 wherein n is one and R is halogen.

6. A compound according to claim 2 wherein R is lower alkyl.

7. A compound according to claim 2 wherein n is one or two.

8. A compound according to claim 2 wherein n is one and R is halogen.

9. A compound according to claim 6 wherein n is one or two.

10. A compound according to claim 6 wherein n is one and R is halogen.

11. A compound according to claim 3 wherein R is methyl or ethyl.

12. A compound according to claim 6 wherein R is methyl or ethyl.

13. A compound according to claim 9 wherein R is methyl or ethyl.

14. A compound according to claim 10 wherein R is methyl or ethyl.

15. A compound according to claim 5 wherein R is fluorine or chlorine.

16. A compound according to claim 8 wherein R is fluorine or chlorine.

17. A compound according to claim 10 wherein R is fluorine or chlorine.

18. The compound l0-chloro-2,3-dihydro-3-methyl-- 7-oxo-7H-pyrido[ 1.2,3-de]- l ,4-benzoxazine-6- carboxylic acid according to claim l7.

19. The compound 2.3-dihydro-9-fluoro-3-methyl-7- oxo-7H-pyrido[l,2,3-de]-l ,4-benzoxazine-6- carboxylic acid according to claim I0.

20. The compound 2,3-dihydro-l0-fluoro-3-methyl- 7-oxo-7H-pyrido[l,2,3-de]- l ,4-benzoxazine-6- carboxylic acid according to claim 17.

21. The compound 9-chloro-2,3-dihydro-3-methyl-7- oxo-7H-pyrido[ l,2,3-de l .4-benzoxazine-6- carboxylic acid according to claim 17.

22. The compound lO-chloro-Z,3-dihydro-3,8- dimethyl-7-oxo-7H-pyridol l,2,3-de]-l ,4-benzoxazineo-carboxylic acid according to claim 9.

23. The compound 2,3-dihydro-3,l0-dimethyl-7-oxo-7H-pyrido[1,2,3-de1-1,4-benzoxazine-6' carboxylic acid according toclaim 9.

24. The compound 9-chloro-2,3-dihydro-3,l0- dimethyl-7-oxo-7H-pyrido[ l,2,3-de]-l ,4-benzoxazinefi-carboxylic acid according to claim 9.

25. The compound 2,3-dihydro-7-oxo-3,8,l0- trimethyl-7H-pyrido{ l,2,3-de]- l ,4-benzoxazine 6- carboxylic acid according to claim 9.

26. The compound 2,3dihydro-3,9dimethyl-7-oxo-7H-pyrido[1,2,3-de]l,4-benzoxazine-o-carboxylic acid according to claim9.

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR3 is hydrogen.
 3. A compound according to claim 1 wherein R1 is loweralkyl.
 4. A compound according to claim 1 wherein n is one or two.
 5. Acompound according to claim 1 wherein n is one and R2 is halogen.
 6. Acompound according to claim 2 wherein R1 is lower alkyl.
 7. A compoundaccording to claim 2 wherein n is one or two.
 8. A compound according toclaim 2 wherein n is one and R2 is halogen.
 9. A compound according toclaim 6 wherein n is one or two.
 10. A compound according to claim 6wherein n is one and R2 is halogen.
 11. A compound according to claim 3wherein R1 is methyl or ethyl.
 12. A compound according to claim 6wherein R1 is methyl or ethyl.
 13. A compound according to claim 9wherein R1 is methyl or ethyl.
 14. A compound according to claim 10wherein R1 is methyl or ethyl.
 15. A compound according to claim 5wherein R2 is fluorine or chlorine.
 16. A compound according to claim 8wherein R2 is fluorine or chlorine.
 17. A compound according to claim 10wherein R2 is fluorine or chlorine.
 18. The compound10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim
 17. 19. The compound2,3-dihydro-9-fluoro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim
 10. 20. The compound2,3-dihydro-10-fluoro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim
 17. 21. The compound9-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxaZine-6-carboxylic acid according to claim
 17. 22. The compound10-chloro-2,3-dihydro-3,8-dimethyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylicacid according to claim
 9. 23. The compound2,3-dihydro-3,10-dimethyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim
 9. 24. Thecompound9-chloro-2,3-dihydro-3,10-dimethyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylicacid according to claim
 9. 25. The compound2,3-dihydro-7-oxo-3,8,10-trimethyl-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim
 9. 26. Thecompound2,3-dihydro-3,9-dimethyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid according to claim 9.